Transcriptional regulation is a major event in cell differentiation, proliferation and apoptosis. Transcriptional activation of a set of genes determines cell destination and for this reason transcription is tightly regulated by a variety of factors. One of its regulatory mechanisms involved in the process is an alteration in the tertiary structure of DNA, which affects transcription factors to their target DNA regiments. Nucleosomal integrity is regulated by the acetylating status of the core histone, with the result being permissiveness to transcription.
The regulations of transcription factor are thought to involve by changes in the structure of chromatin. Changing its affinity of histone proteins for coiled DNA in the nucleosome alters the structure of chromatin. Hypoacetylated histones are believed to have greater affinity to the DNA and form a tightly bound DNA-histone complex and render the DNA inaccessible to transcriptional regulation. The acetylating status of the histone is governed by the balance activities of the histone acetyl transferase (HAT) and histone deacetylase (HDAC).
The first isolation of histone deacetylase was described in 1964 from crude nuclear extracts of cells, but the molecular characterization of isoforms of the enzyme has been achieved recently. Inhibitors of histone deacetylase (HDACs) are zinc hydrolases responsible for the deacetylation of N-acetyl lysine residues of histone and non-histone protein substrates. Human HDACs are classified into two distinct classes, the HDACs and sirtuins. The HDACs are divided into two subclasses based on their similarity to yeast histone deacetylases, RPD 3 (class I includes HDAC 1, 2, 3, 8, and 11) and Hda 1 (class II includes HDAC 4, 6, 7, 9, and 10). All of the HDACs have a highly conserved zinc dependent catalytic domain. There is growing evidence that the acetylation state of proteins and thus the HDAC enzyme family plays a crucial role in the modulation of a number of biological processes, including transcription and cell cycle.
Recently, HDAC inhibitors have been found to arrest growth and apoptosis in several types of cancer cells, including colon cancer, t-cell lymphoma and erythroleukemic cells (M. Paris, et. al., J. Med. Chem., 2008, 51, 1505-1529).
HDAC inhibitor MG3290 was found to be a potent, fungal selective potentiator of several azole antifungals in Aspergillus and Candida species including C. glabrata and also it was found to potentiate azole resistant C-glabrata mutant (WO 2008/021944 and US 2008/0139673).
Given that apoptosis is a crucial factor for cancer progression, HDAC inhibitors are promising reagents for cancer therapy as effective inducers of apoptosis.
Recently, suberoylanilide hydroxamic acid (SAHA) was launched as an antitumor agent for treating cutaneous T-cell lymphoma (CTCL) and is a known HDAC inhibitor. Several structural classes of HDAC inhibitors have been identified and are reviewed in Marks, P. A. et al., J. Natl. Cancer Inst., 2000, 92, 1210-1215. More specifically WO 98/55449 and U.S. Pat. No. 5,369,108 patents report alkanoyl hydroxamates with HDAC inhibitory activity. Other compounds that are able to inhibit HDAC activity are Trichostatin A (TSA), PXD101, Tropoxin (TPX), Sodium butyrate (NaB), Sodium valproate (VPA), Cyclic hydroxamic acid containing peptides (CHAPs), Depsipeptide FK-228, MGCD0103 and MS-275 can derepress these genes, resulting in antiproliferative effects in vitro and anti tumor effects in vivo.    1) WO 2001038322 discloses the compounds and methods for inhibiting histone deacetylase enzymatic activity and have the following formulas I and II.Cy-L′-Ar—Y2—C(O)NH—Z  ICy-L′-Ar—Y3—C(O)NH—Z  IIwherein, Cy is cycloalkyl, aryl, heteroaryl, or heterocyclyl, any of which may be optionally substituted; L2 is C1-C6 saturated alkylene or C1-C6 alkenylene, wherein the alkylene or alkenylene optionally may be substituted: Ar is arylene, wherein said arylene optionally may be additionally substituted. Y2 is a chemical bond or a straight- or branched-chain saturated alkylene, which may be optionally substituted; Z is selected from the group consisting of anilinyl, pyridyl, thiadiazolyl, and —O-M, M being H. L3 is selected from the group consisting of C1-C6 alkylene or C1-C6 alkenylene, wherein the alkylene or alkenylene optionally may be substituted; Y3 is C2-3 alkenylene or C2-3 alkynylene;    2) U.S. Pat. No. 6,624,197 B1 discloses a class of diphenylethylenes of the formula A,
wherein, R is hydrogen or —CO2Z, Z is hydrogen or a cation; and R1, R2 and R3 are each independently H, —OH or —OR4, wherein R4 is linear or branched alkyl of 1-12 carbon atoms; with the condition that when R is hydrogen and R2═R3=—OMe, then R1 is not —OH. The configuration around the double bond may be E/Z. A class of styrenes of the formula B is also provided;
wherein, R5 is hydrogen or methyl; R6 and R7 are independently hydrogen or OMe; R8 is hydrogen or hydroxy. The configuration around the double bond may be E/Z. Pharmaceutical compositions of compounds of the formula A or B are provided for the treatment of diabetes comprising of therapeutically effective amount of the compounds in a physiologically acceptable carrier. A method of treating diabetes is also provided comprising a step of orally administering to a subject suffering from a diabetic condition a therapeutically effective amount of a compound of formula A or B.    3) US 20050038125 describes a method for the treatment and/or prevention of disorders with elevated PGE2 (such as arthritis, fybromyalgia and pain) and/or LTB4 levels (such as asthma, allergy, arthritis, fybromyalgia and inflammation), comprising administering to a mammal an effective amount of pterostilbene component (PS component), a pharmaceutically acceptable salt of PS component or a precursor of PS component, wherein the PS component has the formula C.
In which R1, R2 and R3 are independently selected from hydrogen, C1-50 hydrocarbyl, C1-50 substituted hydrocarbyl, C1-50 heterohydrocarbyl, C1-50 substituted heterohydrocarbyl; and wherein at least one of R1 and R2 is not hydrogen.    4) US 2004/0077726 discloses certain active carbamic acid compounds, which inhibit HDAC activity and have the following formula D,
wherein A is an aryl group; Q1 is a covalent bond or an aryl leader group; J is a sulfonamide linkage selected from: —S(═O)2NR1— and —NR1S(═O)2—; R1 is a sulfonamido substituent; and Q2 is an acid leader group; with the proviso that if J is —S(═O)2NR1—, then Q1 is an aryl leader group; and pharmaceutically acceptable salts, solvates, amides, esters, ethers, chemically protected forms and prodrugs thereof. Pharmaceutical compositions comprising such compounds, and their use to inhibit proliferative conditions are described. Compounds of formula E, wherein Q1 is a covalent bond, J is —NR1SO2—, Q2 is phenylene-meta-trans-ethylene are also described. RB represents fluoro, chloro, methyl, ethyl, isopropyl, t-butyl, trifluoromethyl, hydroxy, methoxy, ethoxy, isopropoxy, methylthio, amino, dimethylamino, diethylamino, morpholino, acetamido, nitro and phenyl. m is an integer from 0 to 4.
    5) WO 2008/054154 discloses a napthalenyloxypropenyl derivative as HDAC inhibitors of the formula 1a-1d wherein R1 is substituted or unsubstituted alkyl groups with one or more substituents.
